Patient-Reported Outcomes in Disorders of Gut-Brain Interaction.

Disorders of gut-brain interaction are characterized by chronic gastrointestinal symptoms in the absence of abnormal endoscopic or radiologic findings or objective biomarkers that can be identified during routine clinical evaluation. The assessment of the symptom pattern and severity, therefore, is the key modality to evaluate the presence, impact, and evolution of these conditions, for both clinical and regulatory purposes. Patient-reported outcomes are structured symptom assessment questionnaires designed to evaluate symptom patterns, quantify severity of symptoms, and evaluate response to treatment at follow-up. This review provides an overview of currently available patient-reported outcomes for evaluating the main disorders of gut-brain interaction, specifically, functional dyspepsia; irritable bowel syndrome; and chronic constipation. It summarizes their content, level of validation for clinical practice and for research, and the regulatory approach to these conditions. Expected future developments and need for further research on patient-reported outcomes for these and other disorders of gut-brain interaction are highlighted.

Efficacy and Findings of a Blinded Randomized Reintroduction Phase for the Low FODMAP Diet in Irritable Bowel Syndrome.

BACKGROUND & AIMS: The efficacy of a low fermentable oligo-, di-, monosaccharides and polyols (FODMAP) diet in irritable bowel syndrome (IBS) is well established. After the elimination period, a reintroduction phase aims to identify triggers. We studied the impact of a blinded reintroduction using FODMAP powders to objectively identify triggers and evaluated the effect on symptoms, quality of life, and psychosocial comorbidities. METHODS: Responders to a 6-week low FODMAP diet, defined by a drop in IBS symptom severity score (IBS-SSS) compared with baseline, entered a 9-week blinded randomized reintroduction phase with 6 FODMAP powders (fructans, fructose, galacto-oligosaccharides, lactose, mannitol, sorbitol) or control (glucose). A rise in IBS-SSS (≥50 points) defined a FODMAP trigger. Patients completed daily symptom diaries and questionnaires for quality of life and psychosocial comorbidities. RESULTS: In 117 recruited patients with IBS, IBS-SSS improved significantly after the elimination period compared with baseline (150 ± 116 vs 301 ± 97, P < .0001, 80% responders). Symptom recurrence was triggered in 85% of the FODMAP powders, by an average of 2.5 ± 2 FODMAPs/patient. The most prevalent triggers were fructans (56%) and mannitol (54%), followed by galacto-oligosaccharides, lactose, fructose, sorbitol, and glucose (respectively 35%, 28%, 27%, 23%, and 26%) with a significant increase in abdominal pain at day 1 for sorbitol/mannitol, day 2 for fructans/galacto-oligosaccharides, and day 3 for lactose. CONCLUSION: We confirmed the significant benefit of the low FODMAP diet in tertiary-care IBS. A blinded reintroduction revealed a personalized pattern of symptom recurrence, with fructans and mannitol as the most prevalent, and allows the most objective identification of individual FODMAP triggers. Ethical commission University hospital of Leuven reference number: s63629; Clinicaltrials.gov number: NCT04373304.

Effects of corticotropin-releasing hormone on gastric electrical activity and sensorimotor function in healthy volunteers: a double-blinded crossover study.

Biopsychosocial factors are associated with disorders of gut-brain interaction (DGBI) and exacerbate gastrointestinal symptoms. The mechanisms underlying pathophysiological alterations of stress remain unclear. Corticotropin-releasing hormone (CRH) is a central regulator of the hormonal stress response and has diverse impact on different organ systems. The aim of the present study was to investigate the effects of peripheral CRH infusion on meal-related gastrointestinal symptoms, gastric electrical activity, and gastric sensorimotor function in healthy volunteers (HVs). In a randomized, double-blinded, placebo-controlled, crossover study, we evaluated the effects of CRH on gastric motility and sensitivity. HVs were randomized to receive either peripheral-administered CRH (100 µg bolus + 1 µg/kg/h) or placebo (saline), followed by at least a 7-day washout period and assignment to the opposite treatment. Tests encompassed saliva samples, gastric-emptying (GE) testing, body surface gastric mapping (BSGM, Gastric Alimetry; Alimetry) to assess gastric myoelectrical activity with real-time symptom profiling, and a gastric barostat study to assess gastric sensitivity to distention and accommodation. Twenty HVs [13 women, mean age 29.2 ± 5.3 yr, body mass index (BMI) 23.3 ± 3.8 kg/m2] completed GE tests, of which 18 also underwent BSGM measurements during the GE tests. The GE half-time decreased significantly after CRH exposure (65.2 ± 17.4 vs. 78.8 ± 24.5 min, P = 0.02) with significantly increased gastric amplitude [49.7 (34.7-55.6) vs. 31.7 (25.7-51.0) µV, P < 0.01], saliva cortisol levels, and postprandial symptom severity. Eleven HVs also underwent gastric barostat studies on a separate day. However, the thresholds for discomfort during isobaric distensions, gastric compliance, and accommodation did not differ between CRH and placebo.NEW & NOTEWORTHY In healthy volunteers, peripheral corticotropin-releasing hormone (CRH) infusion accelerates gastric-emptying rate and increases postprandial gastric response, accompanied by a rise in symptoms, but does not alter gastric sensitivity or meal-induced accommodation. These findings underscore a significant link between stress and dyspeptic symptoms, with CRH playing a pivotal role in mediating these effects.

Diet or medication in primary care patients with IBS: the DOMINO study - a randomised trial supported by the Belgian Health Care Knowledge Centre (KCE Trials Programme) and the Rome Foundation Research Institute.

BACKGROUND: In Europe, IBS is commonly treated with musculotropic spasmolytics (eg, otilonium bromide, OB). In tertiary care, a low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet provides significant improvement. Yet, dietary treatment remains to be explored in primary care. We evaluated the effect of a smartphone FODMAP-lowering diet application versus OB on symptoms in primary care IBS. METHODS: IBS patients, recruited by primary care physicians, were randomised to 8 weeks of OB (40 mg three times a day) or diet and followed for 24 weeks. We compared IBS Symptom Severity Score and the proportion of responders (improvement ≥50 points) in all patients and the subgroup fulfilling Rome IV criteria (Rome+). We also evaluated treatment efficacy, quality of life, anxiety, depression, somatic symptom severity (Patient Health Questionnaire (PHQ15, PHQ9)) and treatment adherence and analysed predictors of response. RESULTS: 459 primary care IBS patients (41±15 years, 76% female, 70% Rome+) were randomised. The responder rate after 8 weeks was significantly higher with diet compared with OB (71% (155/218) vs 61% (133/217), p=0.03) and more pronounced in Rome+ (77% (118/153) vs 62% (98/158), p=0.004). Patients allocated to diet (199/212) were 94% adherent compared with 73% with OB (148/202) (p<0.001). The significantly higher response rate with diet was already observed after 4 weeks (62% (132/213) vs 51% (110/215), p=0.02) and a high symptom response persisted during follow-up. Predictors of response were female gender (OR=2.08, p=0.04) for diet and PHQ15 (OR=1.10, p=0.02) for OB. CONCLUSION: In primary care IBS patients, a FODMAP-lowering diet application was superior to a spasmolytic agent in improving IBS symptoms. A FODMAP-lowering diet should be considered the first-line treatment for IBS in primary care. TRIAL REGISTRATION NUMBER: NCT04270487.

Relationship Between Gastric Emptying Rate and Simultaneously Assessed Symptoms in Functional Dyspepsia.

METHODS: During a GE test (breath test with 13C-octanoic acid labelled 250 kcal solid meal), the severity of 6 symptoms (postprandial fullness, epigastric pain and burning, bloating, nausea and belching) was assessed, every 15 min, before meal-intake and 4h postprandially. The sum of individual symptom scores generated the meal-related symptoms score; the sum of all symptoms generated overall meal-related symptom severity (OSS). Data were compared in patients with normal and delayed GE (cut-off T1/2≥ 109 min). Data are shown as mean±SEM. RESULTS: 504 patients were included, of which 382 patients (67% female, age 43.8±0.8 years, BMI 23.3±0.2 kg/m2) had normal and 122 patients (77% female, age 42.7±1.5 years, BMI 23.2±0.6 kg/m2) had delayed GE. OSS tended to be higher in patients with delayed GE (81.8±3.4 vs. 99.5±7.1, p=.05). Only nausea was significantly higher in patients with delayed GE (11±0.8 vs. 16±1.6, p=.01). No correlations were observed between GE rate and any of the symptoms (OSS: r=0.06, p=.2; nausea: r=0.06, p=.1). The symptom severity time course showed a significant difference only for nausea, with increased severity ratings 90 min after the meal (p<.01) in delayed GE compared to normal GE patients. CONCLUSION: The severity of symptoms in functional dyspepsia and idiopathic gastroparesis, even when assessed during the GE test meal, is not correlated to gastric emptying rate. (Ethics committee University Hospital of Leuven study number S55426).

Evidence-Based and Emerging Dietary Approaches to Upper Disorders of Gut-Brain Interaction.

Food ingestion is a major symptom trigger in functional esophageal and gastroduodenal disorders and gastroparesis. This review summarizes current knowledge and identifies areas of research on the role of food factors and the opportunities for dietary intervention in these disorders. While many patients experiencing functional esophageal and gastroduodenal disorders identify specific food items as symptom triggers, available data do not allow the identification of specific nutrient groups that are more likely to induce symptoms. In functional dyspepsia (FD), recent studies have shown the potential efficacy of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, although the underlying mechanism of action is unclear. Reports of favorable responses to gluten elimination in patients with FD are confounded by the concomitant benefit of reduced intake of fructans, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols present in wheat. Emerging data based on a 6-food elimination diet and confocal laser endomicroscopic evaluation of mucosal responses to food proteins suggest a role for duodenal allergic reactions in FD symptom generation. In patients with gastroparesis, a low-residue diet has been shown to improve symptoms. Novel dietary approaches under evaluation are the Mediterranean diet and the heating/cooling diet approach.

Effects of Rome IV Definitions of Functional Dyspepsia Subgroups in Secondary Care.

BACKGROUND & AIMS: Functional dyspepsia (FD) is subdivided into postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) according to the Rome III consensus. In clinical practice, there is a major overlap between these subgroups. The Rome IV criteria included postprandially occurring symptoms in the PDS subgroup. We aimed to analyze the effects of the Rome IV criteria, compared with Rome III, on FD subgroups in patients recruited from secondary care. METHODS: Patients with FD (n = 224; mean age, 43 ± 1 y; 77% women) were recruited from secondary-care units in Belgium and filled out symptom questionnaires, allowing subdivision according to Rome III and Rome IV criteria and identification of postprandial symptoms. Symptom patterns and demographics were compared between the subgroups. Statistical analysis was performed using the t test and the Fisher exact test. RESULTS: According to the Rome III criteria, 25% of participants had PDS, 8% had EPS, and 67% had an overlap. Postprandial fullness, early satiation, and bloating were present in significantly more patients in the PDS and overlap groups than the EPS group (P < .0001). A higher proportion of patients in the overlap group showed symptoms such as postprandial epigastric pain and nausea than in the EPS group (both P ≤ .02). With the Rome IV criteria, the overlap group was reduced to 35%; 57% of patients were considered to have PDS and 8% to have EPS. Postprandial pain was significantly more prevalent in the PDS than in the EPS group (P ≤ .002), and postprandial nausea was significantly more prevalent in the PDS group than the overlap group (P = .007). CONCLUSIONS: Compared with Rome III criteria, the Rome IV criteria significantly reduces the overlap between PDS and EPS groups. Studies are needed to determine if Rome IV subgroups are associated differently with psychological comorbidities and treatment responses.

Paradigm Shift: Functional Dyspepsia-A "Leaky Gut" Disorder?

ABSTRACT: For up to 2 decades, pathophysiological research in functional dyspepsia focused on gastric sensorimotor dysfunction underlying symptom generation. Recent pathophysiological research has focused on low-grade inflammation in the duodenal mucosa. Emerging evidence confirms a loss of mucosal integrity in the duodenum in functional dyspepsia, and this is confirmed in a confocal laser endomicroscopy study demonstrating altered mucosal barrier function and pyroptosis. This technique may help to establish underlying mechanisms and evaluate novel therapeutic approaches to functional dyspepsia.

Nutrient Drinking Test as Biomarker in Functional Dyspepsia.

INTRODUCTION: Functional dyspepsia (FD) is a prevalent condition with multifactorial pathophysiology, including impaired gastric accommodation (GA), hypersensitivity to gastric distention, and delayed gastric emptying. Drink tests (DT) have been proposed as a potential biomarker for the presence and severity of gastric sensorimotor dysfunction. Thus, we aimed to summarize the state of knowledge on different DT and their potential as a biomarker for FD. METHODS: A PubMed and MEDLINE search was conducted for English language articles, reviews, meta-analyses, case series, and randomized controlled trials, including also published meeting abstracts. RESULTS: Several DT have been described in literature (e.g., different type of liquid, number of calories used, pace of drinking, and subject's awareness of the amount of liquid drunk). FD patients ingest significantly less volume in the different variants of the tests. The slow nutrient ("satiety drinking") test (SDT) studies show the most consistent separation between health and FD and correlation with GA. However, sensitivity to distention may be correlated with rapid DT. SDTs were used to evaluate the effect of several pharmacological agents, often showing concordance between their effects on GA and tolerated nutrient volume. This correlation was not found mainly for agents with central actions. DISCUSSION: An SDT is a potential diagnostic biomarker in FD, reflecting GA. Additional studies are required to confirm its role as a predictive biomarker for treatment outcome in FD.

The Unfulfilled Promise of Prokinetics for Functional Dyspepsia/Postprandial Distress Syndrome.

Functional dyspepsia (FD) is subdivided into epigastric pain syndrome and postprandial distress syndrome according to the Rome IV consensus. Based on the assumption that disordered gastric motility is a key pathophysiologic factor in postprandial distress syndrome, prokinetic agents are often proposed as the treatment of choice for this subgroup. Although a meta-analysis suggests that prokinetic agents may be efficacious and safe in FD, there is a lack of widely available agents of proven efficacy. This review analyzes some of the difficulties and challenges in establishing therapeutic efficacy of prokinetic drugs in FD.

Prucalopride in Gastroparesis: A Randomized Placebo-Controlled Crossover Study.

OBJECTIVES: Prokinetics are considered the preferred treatment option for gastroparesis, but evidence of their efficacy is scarce. Prucalopride, a selective 5-hydroxytryptamine 4 receptor agonist used in the treatment of constipation, is able to enhance the gastric emptying rate. In a double-blind, randomized, placebo-controlled crossover study, we evaluated the efficacy of prucalopride to improve the gastric emptying rate and symptoms in patients with gastroparesis. METHODS: Thirty-four patients with gastroparesis (28 idiopathic, 7 men, mean age 42 ± 13 years) were evaluated in a double-blind crossover trial of 4-week treatment periods with placebo or prucalopride 2 mg q.d., separated by 2 weeks of washout. The primary end point was the change in symptom severity, assessed by the Gastroparesis Cardinal Symptom Index; secondary end points comprised the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index, the Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life, and daily diaries, and the gastric emptying rate was assessed by the C-octanoic acid breath test. RESULTS: Three patients were lost to follow-up. One serious adverse event occurred (small bowel volvulus in the prucalopride group), and 3 patients dropped out because of adverse events of nausea and headache (all prucalopride). For the entire patient group, compared with placebo, prucalopride significantly improved the total Gastroparesis Cardinal Symptom Index (1.65 ± 0.19 vs 2.28 ± 0.20, P < 0.0001) and the subscales of fullness/satiety, nausea/vomiting, and bloating/distention. Prucalopride significantly improved the overall Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life score (1.15 ± 0.16 vs 1.44 ± 0.16, P < 0.05) and the domains of clothing and diet. The gastric half emptying time was significantly enhanced by prucalopride compared with placebo and baseline (98 ± 10 vs 143 ± 11 and 126 ± 13 minutes, P = 0.005 and <0.001, respectively). These significant improvements were also found when considering only the idiopathic gastroparesis subgroup. DISCUSSION: In a cohort of patients with predominantly idiopathic gastroparesis, 4 weeks of prucalopride treatment significantly improved symptoms and quality of life and enhanced gastric emptying compared with placebo.

Gastroduodenal motility disorders.

PURPOSE OF REVIEW: This review summarizes recent progress in the epidemiology, pathophysiology and treatment of gastroduodenal motility disorders with an emphasis on functional dyspepsia and gastroparesis. RECENT FINDINGS: Pathophysiological research has focused on the association of delayed emptying and impaired accommodation with symptom pattern. Studies also confirmed the presence of altered mucosal integrity and low-grade immune activation in the duodenum in functional dyspepsia, while changes in numbers of interstitial cells of Cajal and myenteric neurons were confirmed in gastroparesis. Treatment advances in gastroparesis include new prokinetics such as the ghrelin receptor agonist relamorelin and the antiemetic agent aprepitant. The efficacy and use of neuromodulators were reviewed and new management guidelines for functional dyspepsia were published. SUMMARY: Pathophysiological research has focused on cellular changes in gastroparesis and gastroduodenal motility disorders. New treatments include relamorelin and aprepitant for gastroparesis.

Functional dyspepsia and gastroparesis.

PURPOSE OF REVIEW: This review summarizes recent progress in the epidemiology, pathophysiology and treatment of functional dyspepsia and gastroparesis. RECENT FINDINGS: The definition of functional dyspepsia and its subgroups has been revised in the recent Rome IV consensus. In gastroparesis, the symptom pattern and its similarities and differences from functional dyspepsia have been a focus of recent research. In functional dyspepsia, pathophysiological research continued to evaluate gastric sensorimotor dysfunctions, but low-grade inflammatory changes and loss of mucosal integrity in the duodenum is a new topic of intense research. Treatment advances include new prokinetics such as acotiamide and the ghrelin receptor agonist relamorelin. The efficacy of tricyclic antidepressants was recently reviewed and mirtazapine is a new agent used in the treatment of functional dyspepsia and gastroparesis. In gastroparesis, research has focused on the role of macrophages in loss of interstitial cells of Cajal, and on the role of pyloric resistance as a target for therapy, using botulinum toxin injection and gastric per-endoscopic pyloric myotomy. SUMMARY: The functional dyspepsia definition and subgrouping were updated in the Rome IV consensus. Research focuses on duodenal mucosal alterations in functional dyspepsia and pyloric resistance in gastroparesis. New treatments include novel prokinetics and pylorus-directed interventions.

The Intragastric Pressure Measurement: A Novel Method to Assess Gastric Accommodation in Functional Dyspepsia Children.

BACKGROUND: Impaired gastric accommodation (GA) is proposed as a main pathophysiological mechanism for functional dyspepsia (FD). At present, the gastric barostat is the criterion standard to measure GA. Hence, this procedure is invasive and it may alter gastric physiology. Recently, we proposed the measurement of intragastric pressure (IGP) by means of high-resolution manometry during nutrient intake as a potential alternative for assessing GA in adults. OBJECTIVES: Our aim was first to study the feasibility of the IGP measurement with nutrient tolerance in children with FD and second to compare these results with young healthy adults. METHODS: A high-resolution manometry probe and a feeding tube were positioned in the proximal stomach. The IGP was measured before and during intragastric infusion of a nutrient drink (ND, 300 kcal, 60 mL/min). Subjects were asked to score their satiation and epigastric symptoms. The test ended when the subjects scored maximal satiation. RESULTS: A total of 15 healthy volunteers (HVs, 21.7 ±â€Š4.7 years, 21.1 ±â€Š0.3 kg/m) and 17 patients with FD (14.4 ±â€Š0.7 years, 19.6 ±â€Š0.7 kg/m) participated. Patients with FD experienced mainly from postprandial fullness (86%), epigastric pain (71%), and bloating (62%). In both groups, intragastric infusion of ND induced a drop in IGP (area above the IGP curve FD: -15.5 ±â€Š3.5 mmHg vs HVs: -18.0 ±â€Š8.7 mmHg; P = 0.57). Patients showed impaired nutrient tolerance compared with HVs (587.6 ±â€Š80.2 vs 936 ±â€Š66.2 kcal; P = 0.003). All patients and HVs tolerated the catheters and could finalize the study. CONCLUSIONS: The measurement of IGP during intragastric ND infusion was well tolerated in children. Nutrient tolerance was reduced in children with FD compared with HVs. In the future, this may be a useful tool to assess GA accommodation and nutrient tolerance in children.

Efficacy of Mirtazapine in Patients With Functional Dyspepsia and Weight Loss.

BACKGROUND & AIMS: A subset of patients with functional dyspepsia (FD) present with early satiation and weight loss, for which there are no established therapeutic options. We investigated the efficacy of mirtazapine (an antidepressant and antagonist of the histamine receptor H1, the α2 adrenergic receptor, and the serotonin receptors 5-HT2C and 5-HT-3) in patients with FD and weight loss. METHODS: We conducted a randomized, placebo-controlled pilot trial that studied 34 patients with FD (29 women; mean age, 35.9 ± 2.3 years) with weight loss >10% of original body weight (mean loss, 12.4 ± 2.3 kg) without depression or anxiety. After a run-in period, patients were randomly assigned to groups given placebo (n = 17) or mirtazapine 15 mg each day for 8 weeks (n = 17) in a double-blind manner. Subjects were evaluated during a 2-week baseline and 8-week treatment for dyspepsia symptom severity, quality of life (on the basis of the Nepean Dyspepsia Index), and gastrointestinal-specific anxiety; they were given a nutrient challenge test and weighed. Data were analyzed by using linear mixed models, followed by planned contrasts with adaptive step-down Bonferroni multiple testing correction. RESULTS: Two patients in each group dropped out. At weeks 4 and 8, mirtazapine significantly reduced mean dyspepsia symptom severity scores compared with week 0 (P = .003 and P = .017, respectively); there was no significant reduction in the placebo group (P > .37 for weeks 4 and 8). The difference in change from week 0 between mirtazapine and placebo showed a trend with a large effect size at week 4 (P = .059) that was not significant at week 8 (P = .55). However, improvements from week 0 to weeks 4 and 8 were significantly larger in the mirtazapine group than placebo group for early satiation, quality of life, gastrointestinal-specific anxiety, weight, and nutrient tolerance (mostly with large effect sizes). CONCLUSIONS: In a randomized, placebo-controlled trial, mirtazapine significantly improved early satiation, quality of life, gastrointestinal-specific anxiety, nutrient tolerance, and weight loss in patients with FD. ClinicalTrials.gov number: NCT01240096.